Nicotinic Acetylcholine Receptor Ligands 101

ABSTRACT

Nicotinic acetylcholine receptor ligands of Formula I 
     
       
         
         
             
             
         
       
     
     wherein X, n, R 1  and R 2  are as described in the specification, diastereoisomers, enantiomers, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing, and methods for using the same.

FIELD OF THE INVENTION

This invention relates to furopyridine compounds orpharmaceutically-acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy.The invention relates to compounds that bind to nicotinic acetylcholinereceptors (nAChRs) and particularly to compounds that bind to alpha-7nicotinic acetylcholine receptors.

BACKGROUND OF THE INVENTION

Schizophrenia, clinical anxiety and depression daily affect manymillions of people. These conditions are brain disorders that haveserious and lasting effects on people's lives and impact the sufferersand their friends and relatives.

People with schizophrenia often have trouble thinking clearly or makingdecisions. They may have a hard time telling real life from fantasy.They may have so-called positive symptoms such as delusions orhallucinations which they experience but which do not reflect reality,and see or believe things that are not real; or they may have negativesymptoms and lack behaviors or feelings that normal people have, avoidsocial contact and be emotionally withdrawn. Often they start to dothings, but not follow through and take no pleasure or interest in life;they may be confused in thinking and speech and act in ways that do notmake sense.

People who have generalized anxiety disorder (GAD) worry excessively anduncontrollably about everyday things. This constant worry affects dailyfunctioning and physical symptoms can include sweating, nausea,gastrointestinal discomfort or diarrhea. Sufferers tend to be irritableand complain about feeling on edge, are easily tired and have troublesleeping. GAD can occur with other anxiety disorders, depressivedisorders, or substance abuse. The intensity, duration and frequency ofworrying varies but is disproportionate to the issue and interferes withthe sufferer's performance of tasks and ability to concentrate.

Depressive disorder is an illness that involves the body, mood, andthoughts. It affects the way a person eats and sleeps, the way they feelabout themselves, and the way they think about things. People with adepressive illness cannot merely “pull themselves together” and getbetter. Without treatment, symptoms can last for weeks, months, and evenyears. Major depression interferes with a person's ability to work,study, sleep, eat, and enjoy life. A disabling episode of depression mayoccur only once but more commonly occurs several times in a lifetime. Aless severe type of depression, termed dysthymia, involves long-term,chronic symptoms that do not disable, but keep one from functioning wellor from feeling good. Many people with dysthymia also experience majordepressive episodes at some time in their lives. Bipolar disorder is yetanother type of depression that is also called manic-depressive illness.It is not as prevalent as other forms of depressive disorders andbipolar disorder is characterized by cycling mood changes that swingbetween manic highs and depressive lows. Sometimes the mood switches aredramatic and rapid, but most often they are gradual. When in thedepressed phase, a person can have any or all of the symptoms of adepressive disorder. When in the manic phase, a person may beoveractive, overtalkative, and have a great deal of energy. Manicpersons often think differently and their judgment and social behaviorchanges in ways that cause serious problems and embarrassment; they mayfeel elated, have grand schemes, make unwise business decisions andindulge in romantic sprees. Untreated mania can also evolve into apsychotic state.

Schizophrenia, clinical anxiety and depression are brain disordersthought to arise from the overactivity, underactivity or imbalancedactivity of brain cells. Activities of brain cells and all thinking andfeeling are thought to result from the activities of different brainmessengers interacting with receptors on brain cells. Acetylcholine isone of several messengers by which brain cell communicate with eachother. Acetylcholine interacts with numerous kinds of receptors some ofwhich are the nicotinic acetylcholine receptors that are susceptible tothe actions of nicotine found in tobacco. The use of compounds whichbind nicotinic acetylcholine receptors in the treatment of a range ofdisorders including schizophrenia, anxiety and depression, Alzheimer'sdisease, cognitive or attention disorders, Tourette's syndrome, andParkinson's disease has been discussed in McDonald et al. (1995)“Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry andPharmacology”, Chapter 5 in Annual Reports in Medicinal Chemistry, vol.30, pp. 41-50, Academic Press Inc., San Diego, Calif.; and in Williamset al. (1994) “Neuronal Nicotinic Acetylcholine Receptors,” Drug News &Perspectives, vol. 7, pp. 205-223.

Various nicotinic acetylcholine receptors are known, but one ofparticular interest is the alpha-7 nicotinic acetylcholine receptor andcompounds targeting the alpha-7 receptor are thought to be particularlybeneficial for treating schizophrenia, anxiety and depression.

DESCRIPTION OF THE INVENTION

This invention concerns nicotinic acetylcholine receptor-activecompounds according to Formula I:

wherein:

X is independently selected at each occurrence from CH, O, S, N or NHand at least one X is selected from O, S, N or NH and not more than oneX is O or S;

n is, 0, 1, 2, or 3, and

R¹ and R2 are independently selected at each occurrence from hydrogen,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CF₃, —CONR³R⁴,—CH₂NR³R⁴ or —CH₂OR³;

or, R¹ and R2 together with the nitrogen to which they are attached forma 5- or 6-membered heteroaromatic ring having as ring atoms 1, 2 or 3heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- or6-membered heterocyclic ring having as ring atoms 1, 2 or 3 heteroatomsselected from nitrogen, oxygen and sulfur;

where R³ and R⁴ are independently selected at each occurrence fromhydrogen or —C₁₋₄alkyl, and

where any alkyl, cycloalkyl, alkenyl or alkynyl moiety may besubstituted with 1, 2, 3 or more halogen, —OH or ═O moieties aschemically feasible.

The invention also encompasses stereoisomers, enantiomers, invivo-hydrolysable precursors and pharmaceutically-acceptable salts ofcompounds of Formula I, pharmaceutical compositions and formulationscontaining them, methods of using them to treat diseases and conditionseither alone or in combination with other therapeutically-activecompounds or substances, processes and intermediates used to preparethem, uses of them as medicaments, uses of them in the manufacture ofmedicaments and uses of them for diagnostic and analytic purposes.Compounds described herein selectively bind to alpha-7 nicotinicacetylcholine receptors and thus are particularly useful for treatingschizophrenia, anxiety and depression.

DETAILED DESCRIPTION OF THE INVENTION

Compounds are those according to Formula I:

wherein:

X is independently selected at each occurrence from CH, O, S, N or NHand at least one X is selected from O, S, N or NH and not more than oneX is O or S;

n is, 0, 1, 2, or 3, and

R¹ and R² are independently selected at each occurrence from hydrogen,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CF₃, —CONR³R⁴,—CH₂NR³R⁴ or —CH₂OR³;

or, R¹ and R² together with the nitrogen to which they are attached forma 5- or 6-membered heteroaromatic ring having as ring atoms 1, 2 or 3heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- or6-membered heterocyclic ring having as ring atoms 1, 2 or 3 heteroatomsselected from nitrogen, oxygen and sulfur;

R³ and R⁴ are independently selected at each occurrence from hydrogen or—C₁₋₄alkyl, and

where any alkyl, cycloalkyl, alkenyl or alkynyl moiety may besubstituted with 1, 2, 3 or more halogen, —OH or ═O moieties aschemically feasible;

stereoisomers, enantiomers, in vivo-hydrolysable precursors andpharmaceutically-acceptable salts thereof.

Other compounds are those wherein the moiety

is selected from moieties of Formulae II, III, IV, V or VI

Other compounds are those wherein R¹ and R² are independently selectedfrom hydrogen or methyl.

Other compounds are those wherein n is 1 or 2.

Yet other compounds are those wherein R¹ and R² together with thenitrogen to which they are attached are pyrrolidinyl, piperidinyl,piperazinyl or morpholinyl.

Still other compounds are those wherein the moiety

is selected from moieties of Formulae II, III, IV, V or VI,

R¹ and R2 are independently selected from hydrogen or C₁₋₆alkyl, and

n is 1 or 2.

Particular compounds are those wherein the moiety

is selected from moieties of Formulae II or IV,

R¹ and R² are independently selected from hydrogen or C₁₋₄alkyl, and

n is 1 or 2.

Other particular compounds are those wherein the moiety

is of Formula II,

R¹ and R² are independently selected from hydrogen, methyl or ethyl, and

n is 1 or 2.

Particular compounds are those wherein the moiety

is of Formula IV,

R¹ and R² are independently selected from hydrogen, methyl or ethyl, and

n is 1 or 2.

Particular compounds are those described herein andpharmaceutically-acceptable salts thereof.

Another aspect encompasses compounds according to Formula I wherein oneor more of the atoms is a radioisotope of the same element. In aparticular form of this aspect the compound of Formula I is labeled withtritium. Such radio-labeled compounds are synthesized either byincorporating radio-labeled starting materials or, in the case oftritium, exchange of hydrogen for tritium by known methods. Knownmethods include (1) electrophilic halogenation, followed by reduction ofthe halogen in the presence of a tritium source, for example, byhydrogenation with tritium gas in the presence of a palladium catalyst,or (2) exchange of hydrogen for tritium performed in the presence oftritium gas and a suitable organometallic (e.g. palladium) catalyst.

Compounds labeled with tritium are useful for the discovery of novelmedicinal compounds that bind to and modulate the activity, by agonism,partial agonism, or antagonism, of the alpha-7 nicotinic acetylcholinereceptor. Such tritium-labeled compounds may be used in assays thatmeasure the displacement of such a compounds to assess the binding ofligand that bind to alpha-7 nicotinic acetylcholine receptors.

Another aspect relates to compounds according to Formula I and their usein therapy and to compositions containing them.

Yet another aspect encompasses the use of compounds according to FormulaI for the therapy of diseases mediated through the action of nicotinicacetylcholine receptors. A more particular embodiment of this aspectrelates to the use of compounds of Formula I for the therapy of diseasesmediated through the action of alpha-7 nicotinic acetylcholinereceptors.

Another aspect encompasses a method of treatment or prophylaxis ofdiseases or conditions in which activation of the alpha-7 nicotinicreceptor is beneficial which method comprises administering atherapeutically-effective amount of a compound of Formula I to a subjectsuffering from said disease or condition.

One embodiment of this aspect is a method of treatment or prophylaxis,wherein the disorder is anxiety, schizophrenia, mania or manicdepression.

Another embodiment of this aspect is a method of treatment orprophylaxis of neurological disorders, psychotic disorders orintellectual impairment disorders, which comprises administering atherapeutically effective amount of a compound of Formula I.

Another embodiment of this aspect is a method of treatment orprophylaxis, wherein the disorder is Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, or AttentionDeficit Hyperactivity Disorder.

Another embodiment of this aspect is a method of treatment orprophylaxis, wherein the disorder is Parkinson's disease, Huntington'sdisease, Tourette's syndrome, or neurodegenerative disorders in whichthere is loss of cholinergic synapses.

Another embodiment of this aspect is a method of treatment orprophylaxis of jetlag, nicotine addiction, craving, pain, and forulcerative colitis, which comprises administering a therapeuticallyeffective amount of a compound of Formula I.

Yet another embodiment of this aspect is a method for inducing thecessation of smoking that comprises administering an effective amount ofa compound of Formula I.

Another embodiment of this aspect is a pharmaceutical compositioncomprising a compound of the invention and at least onepharmaceutically-acceptable diluent, lubricant or carrier.

A further aspect relates to a pharmaceutical composition useful fortreating or preventing a condition or disorder mentioned herein arisingfrom dysfunction of nicotinic acetylcholine receptor neurotransmissionin a mammal, preferably a human, comprising an amount of a compound ofFormula I, an enantiomer thereof or a pharmaceutically-acceptable saltthereof, effective in treating or preventing such disorder or condition,and at least one pharmaceutically-acceptable additive diluent, lubricantor carrier.

Another embodiment of this aspect relates to use of a pharmaceuticalcomposition of the invention for the treatment, amelioration orprophylaxis of human diseases or conditions in which activation of theα7 nicotinic receptor is beneficial.

Another embodiment of this aspect is the use of the pharmaceuticalcomposition a compound of Formula I for the treatment or prophylaxis ofneurological disorders, psychotic disorders or intellectual impairmentdisorders.

Another embodiment of this aspect of the invention is the use of thepharmaceutical composition comprising a compound of Formula I for thetreatment or prophylaxis of Alzheimer's disease, learning deficit,cognition deficit, attention deficit, memory loss, Attention DeficitHyperactivity Disorder, anxiety, schizophrenia, or mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,craving, pain, and for ulcerative colitis.

A further aspect is the use of a compound of Formula I, an enantiomerthereof or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for the treatment or prophylaxis of thediseases or conditions mentioned herein.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for the treatment or prophylaxis ofhuman diseases or conditions in which activation of the alpha-7nicotinic receptor is beneficial.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for the treatment or prophylaxis ofneurological disorders, psychotic disorders or intellectual impairmentdisorders.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for treatment or prophylaxis ofAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss or Attention Deficit Hyperactivity Disorder.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for treatment or prophylaxis ofanxiety, schizophrenia, or mania or manic depression.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for treatment or prophylaxis ofParkinson's disease, Huntington's disease, Tourette's syndrome, orneurodegenerative disorders in which there is loss of cholinergicsynapses.

Another embodiment of this aspect is the use of a compound of Formula Iin the manufacture of a medicament for the treatment or prophylaxis ofjetlag, pain, or ulcerative colitis.

Another aspect relates to the use of a compound of Formula I in themanufacture of a medicament for facilitating the cessation of smoking orthe treatment of nicotine addiction or craving including that resultingfrom exposure to products containing nicotine.

Another aspect relates to the use of a compound of Formula I incombination with other therapeutically-active compounds or substances inpharmaceutical compositions or formulations, methods to treat diseasesand conditions, uses as medicaments and uses in the manufacture ofmedicaments. Particular embodiments of this aspect comprise othertherapeutically-active compounds or substances selected from sedatives,hypnotics, anxiolytics, antipsychotics, antianxiety agents,tranquilizers, and the like.

For the uses, methods, medicaments and pharmaceutical compositionsmentioned herein the amount of compound used and the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration and the treatment desired. However, in general,satisfactory results are obtained when the compounds of Formula I areadministered at a daily dosage of from about 0.1 mg to about 20 mg/kg ofanimal body weight. Such doses may be given in divided doses 1 to 4times a day or in sustained release form. For man, the total daily doseis in the range of from 5 mg to 1,400 mg, more preferably from 10 mg to100 mg, and unit dosage forms suitable for oral administration comprisefrom 2 mg to 1,400 mg of the compound admixed with a solid or liquidpharmaceutical carriers, lubricants and diluents.

The compounds of Formula I, an enantiomer thereof, andpharmaceutically-acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect there isprovided a pharmaceutical composition including preferably less than 80%and more preferably less than 50% by weight of a compound of Formula Iin admixture with an inert pharmaceutically-acceptable diluent,lubricant or carrier.

-   Examples of diluents, lubricants and carriers are:    -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   for capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which process comprises mixing theingredients.

Compounds described herein are agonists of nicotinic acetylcholinereceptors. While not being limited by theory, it is believed thatagonists of the alpha-7 nicotinic acetylcholine receptor (nAChR) subtypeare useful in the treatment or prophylaxis of neurological disorders,psychotic disorders and intellectual impairment disorders. The compoundsdescribed herein are indicated as pharmaceuticals, in particular in thetreatment or prophylaxis of neurological disorders, psychotic disordersand intellectual impairment disorders. Examples of psychotic disordersinclude schizophrenia, mania and manic depression, and anxiety. Examplesof intellectual impairment disorders include Alzheimer's disease,learning deficit, cognition deficit, attention deficit, memory loss, andAttention Deficit Hyperactivity Disorder. Compounds described herein mayalso be useful as analgesics in the treatment of pain, chronic pain, andin the treatment or prophylaxis of Parkinson's disease, Huntington'sdisease, Tourette's syndrome, and neurodegenerative disorders in whichthere is loss of cholinergic synapses.

Compounds may further useful for the treatment or prophylaxis of jetlag,for use in inducing the cessation of smoking, craving, and for thetreatment or prophylaxis of nicotine addiction including that resultingfrom exposure to products containing nicotine.

It is also believed that compounds described herein are useful in thetreatment and prophylaxis of ulcerative colitis.

A compound of Formula I or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, or a pharmaceutical compositionor formulation comprising a compound of Formula I may be administeredconcurrently, simultaneously, sequentially or separately with anotherpharmaceutically active compound or compounds selected from thefollowing:

-   (i) antidepressants such as amitriptyline, amoxapine, bupropion,    citalopram, clomipramine, desipramine, doxepin duloxetine,    elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone,    imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone,    paroxetine, phenelzine, protriptyline, reboxetine, robalzotan,    sertraline, sibutramine, thionisoxetine, tranylcypromaine,    trazodone, trimipramine, venlafaxine and equivalents and    pharmaceutically active isomer(s) and metabolite(s) thereof;-   (ii) atypical antipsychotics including for example quetiapine and    pharmaceutically active isomer(s) and metabolite(s) thereof;-   (iii) antipsychotics including for example amisulpride,    aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine,    clozapine, chlorpromazine, debenzapine, divalproex, duloxetine,    eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine,    mesoridazine, olanzapine, paliperidone, perlapine, perphenazine,    phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine,    risperidone, sertindole, sulpiride, suproclone, suriclone,    thioridazine, trifluoperazine, trimetozine, valproate, valproic    acid, zopiclone, zotepine, ziprasidone and equivalents and    pharmaceutically active isomer(s) and metabolite(s) thereof;-   (iv) anxiolytics including for example alnespirone, azapirones,    benzodiazepines, barbiturates such as adinazolam, alprazolam,    balezepam, bentazepam, bromazepam, brotizolam, buspirone,    clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam,    diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam,    fosazepam, lorazepam, lormetazepam, meprobamate, midazolam,    nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate,    trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents    and pharmaceutically active isomer(s) and metabolite(s) thereof;-   (v) anticonvulsants including for example carbamazepine, valproate,    lamotrogine, gabapentin and equivalents and pharmaceutically active    isomer(s) and metabolite(s) thereof;-   (vi) Alzheimer's therapies including for example donepezil,    memantine, tacrine and equivalents and pharmaceutically active    isomer(s) and metabolite(s) thereof;-   (vii) Parkinson's therapies including for example deprenyl, L-dopa,    Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline,    comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake    inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists    and inhibitors of neuronal nitric oxide synthase and equivalents and    pharmaceutically active isomer(s) and metabolite(s) thereof;-   (viii) migraine therapies including for example almotriptan,    amantadine, bromocriptine, butalbital, cabergoline,    dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan,    pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan,    zolmitriptan, zomitriptan, and equivalents and pharmaceutically    active isomer(s) and metabolite(s) thereof;-   (ix) stroke therapies including for example abciximab, activase,    NXY-059, citicoline, crobenetine, desmoteplase, repinotan,    traxoprodil and equivalents and pharmaceutically active isomer(s)    and metabolite(s) thereof;-   (x) urinary incontinence therapies including for example    darafenacin, falvoxate, oxybutynin, propiverine, robalzotan,    solifenacin, tolterodine and and equivalents and pharmaceutically    active isomer(s) and metabolite(s) thereof;-   (xi) neuropathic pain therapies including for example gabapentin,    lidoderm, pregablin and equivalents and pharmaceutically active    isomer(s) and metabolite(s) thereof;-   (xii) nociceptive pain therapies such as celecoxib, etoricoxib,    lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen,    naproxen, paracetamol and equivalents and pharmaceutically active    isomer(s) and metabolite(s) thereof;-   (xiii) insomnia therapies including for example allobarbital,    alonimid, amobarbital, benzoctamine, butabarbital, capuride,    chloral, cloperidone, clorethate, dexclamol, ethchlorvynol,    etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone,    melatonin, mephobarbital, methaqualone, midaflur, nisobamate,    pentobarbital, phenobarbital, propofol, roletamide, triclofos,    secobarbital, zaleplon, zolpidem and equivalents and    pharmaceutically active isomer(s) and metabolite(s) thereof, or-   (xiv) mood stabilizers including for example carbamazepine,    divalproex, gabapentin, lamotrigine, lithium, olanzapine,    quetiapine, valproate, valproic acid, verapamil, and equivalents and    pharmaceutically active isomer(s) and metabolite(s) thereof.

Such combination products employ the compounds of this invention withinthe dosage range described herein and the other pharmaceutically activecompound or compounds within approved dosage ranges and/or the dosagedescribed in the publication reference.

The compounds described herein have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

As used herein, unless otherwise indicated, “C₁₋₆alkyl” includesC₁₋₄alkyl groups but is not limited to methyl, ethyl, n-propyl, n-butyl,i-propyl, i-butyl, t-butyl, s-butyl moieties, whether alone or part ofanother group, C₁₋₄alkyl groups may be straight-chained or branched, andC₃₋₄alkyl groups include cyclic alkyl moieties such as cyclopropyl andcyclobutyl.

As used herein, unless otherwise indicated, “C₂₋₆alkenyl” includesC₂₋₄alkenyl but is not limited to 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl and 3-butenyl.

As used herein, unless otherwise indicated, “C₂₋₆alkynyl” includesC₂₋₄alkynyl but is not limited to ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl and 3-butynyl.

As used herein, unless otherwise indicated, aryl refers to a phenyl ringthat may have 1, 2 or 3 substituents selected from: halogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkyl, CN, NO₂, and CF₃.

As used herein, unless otherwise indicated, heteroaryl refers to a 5- or6-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selectedfrom nitrogen, oxygen and sulfur, and heterocyclyl refers to a 5- or6-membered heterocyclic ring having 1, 2 or 3 heteroatoms selected fromnitrogen, oxygen and sulfur, provided that such heteroaromatic orheterocyclic rings contains at least one nitrogen, oxygen, or sulfuratom.

As used herein, unless otherwise indicated, halogen refers to fluorine,chlorine, bromine, or iodine.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

Unless otherwise stated, reactions are conducted under an inertatmosphere, preferably under a nitrogen atmosphere and are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

Compounds and intermediates may be isolated from their reaction mixturesby standard techniques.

Acid addition salts of the compounds of Formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of Formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

The compounds of Formula I may exist in tautomeric or enantiomericforms, all of which are included within the scope. The various opticalisomers may be isolated by separation of a racemic mixture of thecompounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions that will not causeracemisation.

Pharmacology

The pharmacological activity of compounds of the invention may bemeasured by using tests such as those set out below:

Assay for Affinity at an α₇ nAChR Receptor by Measuring the Binding of¹²⁵I-α-Bungarotoxin (BTX) Binding to Rat Hippocampal Membranes

Rat brain cell membranes bearing α₇ nAChR receptors may be prepared byhomogenizing hippocampus tissue in 20 volumes of cold homogenizationbuffer (HB): mM concentrations of HBconstituents:tris(hydroxymethyl)aminomethane 50; CaCl₂2; MgCl₂ 1; NaCl120; KCl 5: pH 7.4). Homogenates are centrifuged for 5 minutes at1000×g, the supernatant saved and the pellets re-extracted andcentrifuged. Pooled supernatants are centrifuged for 20 minutes at12,000×g, the pelleted membranous material is washed, and re-suspendedin HB. Membranes (30-150 μg) are incubated with 3 nM [¹²⁵I]α-BTX, 1mg/mL bovine serum albumin (BSA), together with test compounds in HB for2 hours at room temperature with gentle shaking. Membranes may then betrapped on Whatman glass fiber filters (thickness C or B) using aBrandel cell harvester and washed 4 times. Pre-treating the filters for3 hours with 1% (BSA/0.01% PEI (polyethyleneimine) in water will yieldlow filter blanks (0.07% of total counts per minute). Non-specificbinding may be determined by 100 μM (−)-nicotine. Typically specificbinding is about 75%.

Assay for Affinity at Human α₇ nAChR Receptor by Measuring the Bindingof ¹²⁵I-α-Bungarotoxin (BTX) Binding to Membranes

Membranes may be prepared from HEK cells expressing human α₇ receptorsby isolating a 500-40000×g membrane fraction. Such membranes may be usedas described for rat brain membranes to assess the binding of compoundsto human α₇ receptors.

Analysis of Binding Data Obtained in α₇ nAChR Receptor Assays

IC₅₀ values and pseudo Hill coefficients (n_(H)) may be calculated usingthe non-linear curve-fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves maybe fitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding a Kd value for[¹²⁵I]-α-BTX binding to rat α7 nAChR of 1.7 nM. K_(i) values may beestimated using the general Cheng-Prusoff equation:

K _(i)=[IC₅₀]/((2+([ligand]/K _(D))^(n))^(1/n)−1)

where a value of n=1 is used whenever n_(H)<1.5 and a value of n=2 isused when n_(H)≧1.5. To account for variability, assays may be performedin triplicate and variability will typically be ±5%. K_(i) values may bedetermined using six to 11 drug concentrations.

Compounds of the invention expected to have useful therapeutic activitywill be found to have binding affinities (K_(i)) of less than 10 μM inα₇ nAChR receptor assays.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

General Experimental Procedures and Conditions

Commercial reagents were used without further purification. Mass spectrawere recorded as m/z for the parent molecular ion unless specifiedotherwise. Room temperature (rt) refers to 20-25° C.

Microwave heating was achieved with a Personal Chemistry SmithSynthesizer or a Personal Chemistry Emrys Optimizer (monomodal, 2.45GHz, 300 W max). Supercritical Fluid Chromatography (SFC) may have beenperformed as a means of purification for selected compounds andintermediates.

LCMS HPLC method was generally performed with an Agilent Zorbax 5μSB-C8column 2.1 mm×5 cm. Solvents: A=H₂O with 2% ACN and 0.1% formic acid,B=2% H₂O with 98% ACN and 0.05% formic acid. Gradient: (0% B through 0.5min., 60% B at 3 min., 95% B at 6 min.).

Abbreviations Used

-   ACN acetonitrile-   AcOH acetic acid-   DCE 1,2-dichloroethane-   DME 1,2-dimethoxyethane-   ES⁺electrospray-   EtOAc ethyl acetate-   EtOH ethanol-   Et₂O diethyl ether-   h hours-   Hz hertz-   HPLC high performance liquid chromatography-   LCMS Liquid Chromatography Mass Spectrometry-   MeOH methanol-   min minutes-   MS mass spectrometry-   m/z mass to charge-   nBuLi n-butyllithium-   rt room temperature-   NMR nuclear magnetic resonance-   THF tetrahydrofuran

Methods of Preparation

Methods that may be used for the synthesis of compounds of Formula I,include the procedures illustrated in Scheme 1 and processes analogousto those described in the Examples. In Scheme 1 X, n, R¹ and R2 are asdefined for compounds of Formula I.

It will be appreciated by those skilled in the art that aromaticsubstituents in the compounds of the invention, or in intermediates usedin the synthesis of compounds of the invention, may be introduced byemploying aromatic substitution reactions, functional grouptransformations to modify existing substituents, or a combinationthereof. Such reactions may be effected either prior to or immediatelyfollowing the processes mentioned above. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic functionalization of an aromatic ring, for example bynitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example by reduction, such as by catalytichydrogenation; acylation, alkylation, sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup by conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group, for example bynucleophilic or organometallically-catalysed substitution reactions.

EXAMPLES Example 1N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine

a) {5-[(dimethylamino)methyl]-2-thienyl}boronic acid

To a suspension of 5-formyl-2-thiopheneboronic acid (500 mg, 3.2 mmol)in DCE (30 mL) was added dimethylamine hydrochloride (520 mg, 6.3 mmol)followed by triethylamine (0.9 mL, 6.5 mmol). The reaction mixture wasstirred for 10 min before sodium triacetoxyborohydride (1.36 g, 6.3mmol) was added in one portion. After the reaction mixture was stirredat room temperature for 5 h, it was quenched with 30 mL of MeOH, stirredbriefly, then concentrated under vacuum. Introduction of a CH₂Cl₂/Et₂Omixture to this residue revealed a solid, which was filtered and washedwith Et₂O. The resulting organic filtrate was concentrated to a viscousoil, which was used without further purification.

b) To a solution of {5-[(dimethylamino)methyl]-2-thienyl}boronic acid(2.23 mmol) in 10 mL of a DME:H₂O:EtOH mixture (7:3:2) was added(2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine](330 mg, 1.11 mmol). The reaction mixture was stirred for severalminutes until homogeneous, at which point Pd(PPh₃)₂Cl₂ (77 mg, 0.11mmol) was added followed by solid Na₂CO₃ (945 mg, 8.92 mmol). Thereaction mixture was purged with N₂ and heated at 65° C. overnight. Thereaction mixture was concentrated by rotary evaporation, thenpartitioned between water and CHCl₃. The organic layer was isolated andthe aqueous layer was extracted 4×50 mL CHCl₃. The combined organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentratedto a viscous oil. The product was chromatographed through silica gel andeluted using 9.5:0.5 CHCl₃ and 7.0 M ammonia in methanol. The titlecompound was further purified by trituration in ether and isolated as asolid (150 mg). ¹H NMR (500 MHz, CD₃OD) δ 1.58-1.65 (m, 1H), 1.74-1.83(m, 2H), 2.04 (bs, 1H), 2.14-2.24 (m, 1H), 2.29 (s, 6H), 2.81-2.87 (m,2H), 2.92-2.98 (m, 2H), 3.07 (d, J=16 Hz, 1H), 3.18 (d, J=17 Hz, 1H),3.28 (d, J=16 Hz, 1H), 3.54 (d, J=17 Hz, 1H), 3.68 (s, 2H), 6.94 (d,J=3.6 Hz, 1H), 7.16 (d, J=3.6 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 8.14 (d,J=2.4 Hz, 1H) MS ES⁽⁺⁾, m/z=356 (M+Na).

Example 2N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

a) {5-[(dimethylamino)methyl]-2-furyl}boronic acid

To a solution of (5-formyl-2-furyl)boronic acid (50 mg, 0.36 mmol) inDME (1.0 mL) was added a 2.0M solution of dimethylamine in THF (0.53 mL,1.0 mmol). The reaction mixture stirred for 5 minutes before resin boundMP-BH(OAc)₃ (2.2 mmol/g, 0.33 g, 0.714 mmol) was added. The reactionmixture was stirred at room temperature for five hours and an additional1 equivalent of dimethylamine in THF was added and stirring continuedovernight. The reaction mixture was filtered through a plug of glasswool and the resin was washed with DME. The THF/DME filtrate solutioncontaining the desired compound was used immediately in subsequentreactions.

b) To a solution of {5-[(dimethylamino)methyl]-2-furyl}boronic acid(0.25 mmol) in 2.5 mL of a DME:H₂O:EtOH mixture (7:3:2) was added(2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine](37 mg, 0.12 mmol). The reaction mixture was stirred for several minutesuntil homogeneous, at which point Pd(PPh₃)₂Cl₂ (9 mg, 0.012 mmol) wasadded followed by solid Na₂CO₃ (53 mg, 0.5 mmol). The reaction mixturewas purged with N₂ and heated at 65° C. for 4.5 h. The reaction mixturewas partitioned between water and CHCl₃. The organic layer was isolatedand the aqueous layer was extracted 2×50 mL CHCl₃. The combined organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The product was purified by preparative plate chromatography using9.0:1.0 CHCl₃ and 7.0 M ammonia in methanol as the eluant. The titlecompound was isolated as viscous oil (30 mg). ¹H NMR (500 MHz, CD₃OD) δ1.59-1.63 (m, 1H), 1.73-1.82 (m, 2H), 2.04 (bs, 1H), 2.18-2.22 (m, 1H),2.29 (s, 6H), 2.83-2.86 (m, 2H), 2.92-2.95 (m, 2H), 3.06 (d, J=16 Hz,1H), 3.18 (d, J=16 Hz, 1H), 3.26 (d, J=16 Hz, 1H), 3.54 (d, J=16 Hz,1H), 3.68 (s, 2H), 6.38 (d, J=3.2 Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 7.91(d, J=2 Hz, 1H), 8.26 (d, J=2 Hz, 1H) MS ES⁽⁺⁾, m/z=340 (M+Na).

Alternatively,N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenaminecan be prepared via the aldehyde by the method given below.

a)5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furaldehyde

To a solution of(2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine](6 g, 20.3 mmol) in 400 mL of a DME:H₂O:EtOH mixture (7:3:2) was added5-formyl-2-furanboronic acid (5.67 g, 40.5 mmol). The reaction mixturewas purged with N₂ (directly into the solvent) and stirred for tenminutes until homogeneous. Solid Na₂CO₃ (8.6 g, 81.0 mmol) was added tothe reaction mixture followed by Pd(PPh₃)₂Cl₂ (711 mg, 1.0 mmol). Thereaction mixture was again purged with N₂ for 10 min, then heated at 65°C. for 6 h. The reaction mixture was stirred at rt overnight, thenconcentrated via rotary evaporator. The resulting residue was dilutedwith CHCl₃ and filtered through diatomaceous earth. The CHCl₃ filtratewas concentrated and the resulting residue was diluted with 1N HCl andextracted with EtOAc (3×150 mL). The acidic aqueous layer was made basicwith the addition of 2N aqueous NaOH (to pH˜12) and the basic aqueoussolution was extracted with CHCl₃ (3×150 mL). The combined CHCl₃ layerwas washed with brine, dried (Na₂SO₄), filtered and concentrated to asolid (5.79 g, 92% yield). This material was used without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 1.46-1.53 (m, 1H), 1.68-1.71 (m,2H), 2.03-2.04 (m, 1H), 2.22-2.26 (m, 1H), 2.78-2.94 (m, 3H), 2.97 (d,J=14.7 Hz, 1H), 3.00 -3.04 (m, 1H), 3.07 (d, J=16.5 Hz, 1H), 3.40 (d,J=14.7 Hz, 1H), 3.47 (d, J=16.5 Hz, 1H), 6.74 (d, J=3.7 Hz, 1H), 7.30(d, J=3.7 Hz, 1H), 7.89 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H) MS ES⁺,m/z=311 (M+H⁺).

b)N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

To a solution of5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furaldehyde(5.8 g, 18.7 mmol) in methanol (180 mL) at room temperature under N₂ wasadded dimethylamine (18.7 mL of a 2.0 M THF solution, 37.3 mmol). Thereaction mixture was stirred for 30 min at rt before AcOH (4.3 mL, 74.7mmol) was added followed by the portionwise addition of NaBH₃CN (1.74 g,28.0 mmol). The reaction mixture was then stirred at rt for 4 h, thenconcentrated via rotary evaporation. The resulting residue was dilutedwith saturated aqueous K₂CO₃ and extracted with CHCl₃ (4×100 mL). Thecombined CHCl₃ layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated to a viscous residue. The product was purified by columnchromatography (SiO₂) using 9.5:0.5 CHCl₃ and 7.0 M ammonia in MeOH toelute the desired compound.

Example 3N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine

The compound of Example 3 was prepared by a process analogous to thatused for Example 1, as detailed below.

a) 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine

To a solution of 4-bromothiophene-2-carboxyaldehyde (5 g, 26.3 mmol) inEtOH (130 mL) at rt and under N₂ was added the dimethylamine in THF (20mL of a 2.0 M solution, 40 mmol) followed by AcOH (1.9 mL). NaBH₃CN (2.1g, 34 mmol) was then added in portions to the reaction mixture over a 5min period and the reaction mixture was stirred overnight at rt. Thereaction mixture was diluted with saturated NaHCO₃ and extracted withCHCl₃ (3×50 mL). The combined organic layer was concentrated and theresulting residue was diluted with 1 N HCl and washed with CHCl₃. Theacidic aqueous layer was then made basic with the addition of saturatedNaHCO₃ and extracted with CHCl₃ (3×50 mL). The combined organic layerwas washed with brine, dried (Na₂SO₄), filtered and concentrated (86%yield). The product was used without further purification. ¹H NMR (500MHz, CD₃OD) δ 2.26 (s, 6H), 3.65 (s, 2H), 6.92 (apparent s, 1H), 7.31(d, J=2 Hz, 1H).

b) Diisopropyl {5-[(dimethylamino)methyl]-3-thienyl}boronate

To a solution of 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine (2.8 g,12.8 mmol) in THF (130 mL) at −78° C. under N₂ was addedtri-isopropylborate (4.4 mL, 19.2 mmol). The reaction mixture wasstirred briefly before nBuLi (12 mL of a 1.6 M hexane solution) wasadded dropwise via syringe. The reaction mixture then stirred for 6.5 hat −78 ° C. before being concentrated by rotary evaporation. Theresulting white solid was used without further purification.

c)N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine

To a solution of diisopropyl{5-[(dimethylamino)methyl]-3-thienyl}boronate (3.6 g, 13 mmol) in 120 mLof a DME:H₂O:EtOH mixture (7:3:2) was added(2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine](2.0 g, 6.75 mmol). The reaction mixture was purged with N₂ and stirredfor several min until homogeneous, at which point Na₂CO₃ (2.9 g, 27mmol) was added, followed by Pd(PPh₃)₂Cl₂ (236 mg, 0.34 mmol). Thereaction mixture was purged with N₂ for 10 min, then heated at 75° C.for 2 h and at rt overnight. The reaction mixture was concentrated byrotary evaporation. The resulting residue was diluted with CHCl₃ andfiltered though diatomaceous earth. The organic filtrate wasconcentrated and the resulting residue was diluted with 1 N HCl andextracted with EtOAc (3 times). The acidic aqueous layer was then madebasic with the addition of 2 N NaOH and extracted with CHCl₃ (4×100 mL).The combined organic layer was washed with brine, dried (Na₂SO₄),filtered and concentrated to a viscous oil. The product waschomatographed though silica gel and eluted using 9.5:0.5 CHCl₃ and 7.0M ammonia in methanol. The title compound was further purified bytrituration in Et₂O and isolated (1.5 g, 62% yield). ¹H NMR (500 MHz,CD₃OD) δ 1.58-1.64 (m, 1H), 1.73-1.82 (m, 2H), 2.04 (bs, 1H), 2.18-2.24(m, 1H), 2.30 (s, 6H), 2.83-2.86 (m, 2H), 2.93-2.98 (m, 2H), 3.06 (d,J=14.6 Hz, 1H), 3.18 (d, J=16.5 Hz, 1H), 3.26 (d, J=14.6 Hz, 1H), 3.54(d, J=17 Hz, 1H), 3.71 (s, 2H), 7.28 (s, 1H), 7.50 (s, 1H), 7.88 (s,1H), 8.17 (s, 1H) MS ES⁺, m/z=356 (M+Na⁺).

Example 4N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

The compound of Example 4 may be prepared by a process analogous to thatused for Example 2.

Example 5N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine

The compound of Example 5 may be prepared by a method analogous to thealternate method of Example 2, or prepared according to Scheme 2 asdetailed below.

a)5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde

To a stirred solution of(2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine](Scheme 1, 3.2 g, 10.8 mmol) and (5-formyl-2-thienyl)boronic acid (3.37g, 21.6 mmol) in 150 mL DME/H₂O/EtOH (7:3:2), powdered Na₂CO₃ (4.58 g,43.2 mmol) was added. The resulting mixture was purged with N₂ at rt for15 min, before the addition ofdichloro[bis(triphenylphosphoranyl)]palladium (380 mg, 0.54 mmol). Thereaction mixture was purged with N₂ for another 15 min, before beingheated in a 70° C. oil bath under N₂ for 3-4 h. The reaction mixture wascooled and then concentrated under reduced pressure. The solid residuewas treated with 150 mL CHCl₃, and the resulting suspension was filteredthrough a short pad of diatomaceous earth (the filter cake was washedwith ˜100 mL CHCl₃). The combined filtrate was concentrated underreduced pressure. The blackish solid was taken into 0.5 M HCl (100-150mL) and EtOAc (˜100 mL). The acidic aqueous layer was separated and theblackish organic layer was washed further with 0.5 M HCl (2×50mL). Thecombined aqueous layers were then basified with 1 M NaOH to pH ˜12, andextracted with CHCl₃ (100 mL, then 2×50 mL). The CHCl₃ extracts weredried over MgSO₄, filtered, and concentrated to give 3.5 g (99%) of5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde.¹H NMR (500 MHz, CDCl₃) δ 1.50 (dddd, J=12.8, 10.7, 6.7, 2.3 Hz, 1H),1.68-1.72 (m, 2H), 2.03 (t, J=2.9 Hz, 1H), 2.22-2.26 (m, 1H), 2.78-2.95(m, 3H), 2.97 (dd, J=14.7, 2.1 Hz, 1H), 3.01-3.05 (m, 1H), 3.08 (d,J=16.5 Hz, 1H), 3.40 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (d, J=16.5 Hz, 1H),7.29 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H),8.36 (d, J=2.2 Hz, 1H), 9.88 (s, 1H); MS ES⁺ m/z=327 (M+H⁺).

b) To a stirred suspension of5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde(1.5 g, 4.6 mmol) in 40 mL MeOH, 9.2 mL methylamine methanolic solution(18.4 mmol) was added. The clear solution was stirred at rt for 0.5 hbefore the addition of NaBH₄ (524 mg, 3.0 equiv) as one portion. Thereaction mixture was stirred at rt for 1 h. The solution wasconcentrated under reduced pressure to give a black residue, which wasdissolved in 60 mL MeOH and treated with 30 mL 4.0 M HCl. The resultingsolution was heated at 80° C. for 1-2 h. MeOHl was removed under reducedpressure. The resulting acidic aqueous solution was basified by slowaddition of conc. aqueous NaOH until pH>12 and extracted with CHCl₃(3×50 mL). The blackish organic layers were dried over MgSO₄, filteredand concentrated to give a black residue, which was then purified byshort-packed silica gel column (5% 7 M NH₃/MeOH in CHCl₃) to give ayellowish solid, which was washed with minimum amount of Et₂O (˜20 mL)to remove minor impurities. Yield: 1.2 g (76%); ¹H NMR (500 MHz, CDCl₃)δ 1.48 (ddd, J=12.8, 10.7, 6.6, 2.3 Hz, 1H), 1.67-1.70 (m, 2H), 2.02 (t,J=2.9 Hz, 1H), 2.22-2.27 (m, 1H), 2.50 (s, 3H), 2.77-2.93 (m, 3H), 2.96(dd, J=14.7, 2.1 Hz, 1H), 3.01-3.07 (m, 1H), 3.04 (d, J=16.2 Hz, 1H),3.39 (dd, J=14.7, 1.8 Hz, 1H), 3.43 (d, J=16.2 Hz, 1H), 3.93 (s, 1H),6.87 (d, J=3.6 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H),8.23 (d, J=2.2 Hz, 1H); MS ES⁺ m/z=342 (M+H⁺).

Example 6N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.21]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

This compound was prepared by a process analogous to that used forExample 5, via Scheme 2. ¹H NMR (500 MHz, CDCl₃) δ 1.44-1.50 (m, 1H),1.67-1.70 (m, 2H), 2.00-2.03 (m, 1H), 2.22-2.27 (m, 1H), 2.48 (s, 3H),2.79-3.04 (m, 6H), 3.42 (d, J=16.3 Hz, 1H), 3.39 (d, J=15.6 Hz, 1H),3.78 (s, 2H), 6.24 (d, J=3.1 Hz, 1H), 6.45 (d, J=3.1 Hz, 1H), 7.69 (s,1H), 8.31 (s, 1H); MS ES⁺, m/z=326 (M+H⁺)

Example 7(2R)-5′-[5-(pyrrolidin-1-ylmethyl)-2-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine]

A process analogous to the alternate preparation for Example 2 was usedto prepare this compound. ¹H NMR (300 MHz, CDCl₃) δ 1.42-1.52 (dddd,J=2.6, 6.8, 10.2, 12.8 Hz, 1H), 1.66-1.71 (m, 2H), 1.77-1.83 (m, 4H),1.98-2.03 (m, 1H), 2.21-2.28 (m, 1H), 2.57-2.63 (m, 4H), 2.79-3.05 (m,6H), 3.39 (d, J=14.6 Hz, 1H), 3.42 (d, J=16.3 Hz, 1H), 3.68 (s, 2H),6.25 (d, J=3.2 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H),8.31 (d, J=2.2 Hz, 1H); MS ES⁺, m/z=366 (M+H⁺)

Example 8(2R)-5′-[5-(morpholin-4-ylmethyl)-2-furyl]-3′H-spiro[14-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine]

A process analogous to the alternate preparation for Example 2 was usedto prepare this compound. ¹H NMR (300 MHz, CDCl₃) δ 1.42-1.50 (m, 1H),1.66-1.71 (m, 2H), 2.00-2.04 (m, 1H), 2.20-2.28 (m, 1H), 2.53 (t, J=4.6Hz, 4H), 2.82-3.06 (m, 6H), 3.39 (d, J=13.8 Hz, 1H), 3.43 (d, J=16.3 Hz,1H), 3.59 (s, 2H), 3.73 (t, J=4.6 Hz, 4H), 6.28 (d, J=3.4 Hz, 1H), 6.46(d, J=3.4 Hz, 1H), 7.70 (s, 1H), 8.32 (s, 1H); MS ES⁺, m/z=382 (M+H⁺).

Example 9N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

A process analogous to the alternate preparation for Example 2 was usedto prepare this compound, utilizing 5-formylfuran-3-boronic acid pinacolester in the Suzuki coupling in place of the free boronic acid. ¹H NMR(500 MHz, CD₃OD) δ 1.57-1.63 (m, 1H), 1.72-1.82 (m, 2H), 2.04 (bs, 1H),2.15-2.22 (m, 1H), 2.29 (s, 6H), 2.83-2.87 (m, 2H), 2.92-2.97 (m, 2H),3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H), 3.26 (d, J=14.6 Hz, 1H),3.53 (d, J=18 Hz, 1H), 3.54 (s, 2H), 6.66 (s, 1H), 7.78 (d, J=2 Hz, 1H),7.82 (s, 1H), 8.07 (d, J=2 Hz, 1H) MS ES⁺, m/z=340 (M+Na⁺).

Example 10(2R)-5′-[5-(pyrrolidin-1-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine]

This compound was prepared by a process analogous to that used forExample 9,N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine.¹H NMR (500 MHz, CD₃OD) δ 1.57-1.63 (m, 1H), 1.74-1.85 (m, 6H), 2.03(bs, 1H), 2.17-2.22 (m, 1H), 2.62-2.64 (m, 4H), 2.81-2.87 (m, 2H),2.92-2.97 (m, 2H), 3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H), 3.26(d, J=14.6 Hz, 1H), 3.53 (d, J=16.5 Hz, 1H), 3.69 (s, 2H), 6.64 (s, 1H),7.77 (d, J=2 Hz, 1H), 7.81 (s, 1H), 8.07 (d, J=2 Hz, 1H) MS ES⁺, m/z=366(M+Na⁺).

Example 11(2R)-5′-[5-(morpholin-4-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine]

This compound was prepared by a process analogous to that used forExample 9,N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine.¹H NMR (500 MHz, CD₃OD) δ 1.57-1.63 (m, 1H), 1.72-1.81 (m, 2H), 2.03(bs, 1H), 2.18-2.22 (m, 1H), 2.51-2.53 (m, 4H), 2.80-2.86 (m, 2H),2.92-2.97 (m, 2H), 3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H), 3.26(d, J=14.6 Hz, 1H), 3.53 (d, J=16.5 Hz, 1H), 3.59 (s, 2H), 3.68-3.70 (m,4H), 6.66 (s, 1H), 7.77 (d, J=2 Hz, 1H), 7.82 (s, 1H), 8.07 (d, J=2 Hz,1H) MS ES⁺, m/z=382 (M+Na⁺).

Example 12N-methyl-N-({5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine

To a stirred solution ofN-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine(140 mg, 0.4 mmol) as prepared in Example 6 in 7 mL MeOH,[(1-ethoxycyclopropyl)oxy](trimethyl)silane (410 mg) was added, followedby addition of AcOH (340 mg, 5.6 mmol) and NaBH₃CN (130 mg, 2.0 mmol).The reaction mixture was heated at 65° C. oil bath overnight. It wasthen cooled to rt and concentrated under reduced pressure. The residuewas quenched with aqueous potassium carbonate solution and extractedwith CHCl₃ (3×30 mL). The organic layers were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue wasthen purified by silica gel column chromatography (5% 7M NH₃/MeOH inCHCl₃) to give the title compound (90 mg, 62% yield). ¹H NMR (500 MHz,CDCl₃) δ 0.41-0.49 (m, 4H), 1.47 (dddd, J=2.4, 6.7, 10.4, 12.8 Hz, 1H),1.67-1.70 (m, 2H), 1.73 (m, 1H), 1.99-2.01 (m, 1H), 2.21-2.27 (m, 1H),2.39 (s, 3H), 2.78-2.92 (m, 3H), 2.95 (dd, J=2.4, 14.7 Hz, 1H), 3.03 (d,J=16.5 Hz, 1H), 3.00-3.06 (m, 1H), 3.39 (d, J=14.7 Hz, 1H), 3.42 (d,J=16.5 Hz, 1H), 3.73 (s, 2H), 6.24 (d, J=3.3 Hz, 1H), 6.46 (d, J=3.3 Hz,1H), 7.69 (d, J=1.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H); MS ES⁺, m/z=366(M+H⁺).

Example 13N-methyl-N-({4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine

This compound was prepared by a process analogous to that used forExample 12. ¹H NMR (500 MHz, CD₃OD) δ 0.40-0.42 (m, 2H), 0.49-0.51 (m,2H), 1.58-1.63 (m, 1H), 1.74-1.82 (m, 3H), 2.04 (bs, 1H), 2.18-2.23 (m,1H), 2.36 (s, 3H), 2.82-2.86 (m, 2H), 2.94-2.97 (m, 2H), 3.06 (d, J=16Hz, 1H), 3.16 (d, J=16.5 Hz, 1H), 3.26 (d, J=15 Hz, 1H), 3.53 (d, J=16.5Hz, 1H), 3.72 (s, 2H), 6.63 (s, 1H), 7.78 (d, J=2 Hz, 1H), 7.81 (s, 1H),8.08 (d, J=2 Hz, 1H) MS ES⁺, m/z=366 (M+Na⁺).

The compounds of Examples 14, 15 and 16 may be prepared by the processof Scheme 1, or as specifically described.

Example 141-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

To a hydrogenation vessel, a spatula tip of Ra—Ni in aqueous suspensionwas added. The catalyst was washed with MeOH (2×2 mL), before theaddition of 5 mL Methanolic solution of 100 mg (0.32 mmol)5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furaldehydeand 10 mL 7 M NH₃ in MeOH. The hydrogenation reaction was carried out ina Parr shaker (50 psi, 45° C., 2-3 h). The catalyst was filtered off,and the filtrate was concentrated under reduced pressure. The residuewas then purified by silica gel column chromatography (18% MeOH, 2%NH₄OH in CHCl₃ as eluent) to give the title compound (63 mg, 63% yield).¹H NMR (500 MHz, CDCl₃) δ 1.44-1.51 (dddd, J=2.4, 6.7, 10.4, 12.8 Hz,1H), 1.66-1.70 (m, 2H), 2.00-2.03 (m, 1H), 2.21-2.28 (m, 1H), 2.77-2.93(m, 3H), 2.95 (dd, J=2.4, 14.7 Hz, 1H), 3.02 (d, J=16.5 Hz, 1H),3.00-3.07 (m, 1H), 3.39 (d, J=14.7 Hz, 1H), 3.43 (d, J=16.5 Hz, 1H),3.87 (s, 2H), 6.20 (d, J=3.4 Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 7.69 (s,1H), 8.31 (s, 1H) MS ES⁺, m/z=312 (M+H⁺).

Example 151-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine

To a solution of5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde(326 mg, 1.0 mmol) in 10 mL MeOH, 0.2 mL 50% hydroxylamine aqueoussolution (3.0 mmol) was added. The reaction mixture was stirred at rtfor 2 h, then was concentrated under reduced pressure to give the oximeintermediate (300 mg, 88%), which was used without any furtherpurification.

To a stirred solution of oxime (280 mg, 0.8 mmol) in AcOH (4 mL), Znpowder (390 mg, 6 mmol) was added. The reaction mixture was stirred atrt for 1 h (progress was monitored by LCMS). It was then diluted withMeOH and filtered. The filtrate was concentrated under reduced pressure.The residue was quenched with aqueous potassium carbonate solution andextracted with CHCl₃ (3×30 mL). The organic layers were combined, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was then purified by silica gel column chromatography (18% MeOH,2% NH₄OH in CHCl₃ as eluent) to give the title compound (0.26 g, 99%yield). ¹H NMR (500 MHz, CDCl₃) δ 1.47 (dddd, J=2.4, 6.7, 10.4, 12.8 Hz,1H), 1.68-1.71 (m, 2H), 2.01-2.04 (m, 1H), 2.23-2.27 (m, 1H), 2.78-2.93(m, 3H), 2.96 (dd, J=2.4, 14.7 Hz, 1H), 3.01-3.07 (m, 1H), 3.04 (d,J=16.3 Hz, 1H), 3.40 (dd, J=1.2, 14.7 Hz, 1H), 3.44 (d, J=16.3 Hz, 1H),4.05 (s, 2H), 6.86 (d, J=3.6 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.59 (s,1H), 8.22 (s, 1H); MS ES⁺, m/z=328 (M+H⁺)

Example 161-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine

This compound was prepared by a process analogous to that used forExample 15. ¹H NMR (300 MHz, CD₃OD) δ 1.55-1.65 (m, 1H), 1.69-1.87 (m,2H), 2.03 (s, 1H), 2.12-2.25 (m, 1H), 2.81-2.97 (m, 2H), 3.06 (d, J=14.7Hz, 1H), 3.15 (d, J=16.7 Hz, 1H), 3.27 (d, J=14.7 Hz, 1H), 3.51 (d,J=16.7 Hz, 1H), 3.80 (s, 2H), 6.59 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79(s, 1H), 8.05 (d, J=1.8 Hz, 1H); MS ES⁺ m/z=312 (M+H⁺)

1. A compound in accord with Formula I:

wherein: X is independently selected at each occurrence from CH, O, S, Nor NH and at least one X is selected from O, S, N or NH and not morethan one X is O or S; n is 0, 1, 2, or 3, and R¹ and R² areindependently selected from hydrogen, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —CF₃, —CONR³R⁴, —CH₂NR³R⁴ or —CH₂OR³; or, R¹and R2 together with the nitrogen to which they are attached form a 5-or 6-membered heteroaromatic ring having as ring atoms 1, 2 or 3heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- or6-membered heterocyclic ring having as ring atoms 1, 2 or 3 heteroatomsselected from nitrogen, oxygen and sulfur; R³ and l⁴ are independentlyselected at each occurrence from hydrogen or —C₁₋₄alkyl, and where anyalkyl, cycloalkyl, alkenyl or alkynyl moiety may be substituted with 1,2, 3 or more halogen, —OH or ═O moieties as chemically feasible, or astereoisomer, enantiomer, in vivo-hydrolysable precursor orpharmaceutically-acceptable salt thereof.
 2. A compound according toclaim 1, wherein the moiety

is selected from moieties of Formulae II, III, IV, V or VI

or a stereoisomer, enantiomer, in vivo-hydrolysable precursor orpharmaceutically-acceptable salt thereof.
 3. A compound according toclaim 1, wherein R¹and R² are independently selected from hydrogen ormethyl; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor orpharmaceutically-acceptable salt thereof.
 4. A compound according toclaim 1, wherein n is 1 or 2; or a stereoisomer, enantiomer, invivo-hydrolysable precursor or pharmaceutically-acceptable salt thereof.5. A compound according to claim 1, wherein R¹ and R² together with thenitrogen to which they are attached are selected from pyrrolidinyl,piperidinyl, piperazinyl or morpholinyl; or a stereoisomer, enantiomer,in vivo-hydrolysable precursor or pharmaceutically-acceptable saltthereof.
 6. A compound according to claim 1, wherein the moiety

is selected from moieties of Formulae II, III, IV, V or VI,

R¹ and R² are independently selected from hydrogen or methyl, and n is 1or 2; or a stereoisomer, enantiomer, in vivo-hydrolysable precursor orpharmaceutically-acceptable salt thereof.
 7. A compound according toclaim 1, wherein: the moiety

is a moiety of Formula II or IV, R¹ and R² are independently selectedfrom hydrogen or methyl, and n is 1 or
 2. 8. A compound according toclaim 1, wherein: the moiety

is of Formula II, R¹ and R² are independently selected from hydrogen ormethyl, and n is 1 or
 2. 9. A compound according to claim 1, wherein:the moiety

is of Formulae I, R¹ and R² are independently selected from hydrogen ormethyl, and n is 1 or
 2. 10. A compound selected from the groupconsisting ofN,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine;N,N-dimethyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine;N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]2-furyl}methenamine;(2R)-5′-[5-(pyrrolidin-1-ylmethyl)-2-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];(2R)-5′-[5-(morpholin-4-ylmethyl)-2-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];N,N-dimethyl-1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;(2R)-5′-[5-(pyrrolidin-1-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];(2R)-5′-[5-(morpholin-4-ylmethyl)-3-furyl]-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine];N-methyl-N-({5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine;N-methyl-N-({4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methyl)cyclopropanamine;1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methenamine,and1-{4-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-furyl}methenamine;or a stereoisomer, enantiomer, in vivo-hydrolysable precursor orpharmaceutically-acceptable salt of any foregoing compound.
 11. A methodof treatment or prophylaxis of a disease or condition in whichactivation of the α7 nicotinic receptor is beneficial which methodcomprises administering a therapeutically-effective amount of a compoundor a pharmaceutically-acceptable salt thereof according to claim 1 to asubject suffering from said disease or condition.
 12. The method ofclaim 11, wherein said disease or condition is anxiety, schizophrenia,mania or manic depression.
 13. A method of treatment or prophylaxis ofneurological disorders, psychotic disorders or intellectual impairmentdisorders, which comprises administering a therapeutically effectiveamount of a compound or a pharmaceutically-acceptable salt thereofaccording to claim
 1. 14. The method of claim 11, wherein said disorderis Alzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, Attention Deficit Hyperactivity Disorder,Parkinson's disease, Huntington's disease, Tourette's syndrome,neurodegenerative disorders in which there is loss of cholinergicsynapses, jetlag, nicotine addiction, craving, pain, or ulcerativecolitis.
 15. A method for inducing the cessation of smoking comprisingadministering an effective amount of a compound or apharmaceutically-acceptable salt thereof according to claim
 1. 16. Apharmaceutical composition comprising a compound or apharmaceutically-acceptable salt thereof according to claim 1 and atleast one pharmaceutically-acceptable diluent, lubricant or carrier. 17.A method of treatment or prophylaxis of a disease or condition in whichactivation of the alpha-7 nicotinic receptor is beneficial which methodcomprises administering a therapeutically-effective amount of apharmaceutical composition according to claim 16 to a subject sufferingfrom said disease or condition.
 18. The method of claim 17, wherein saiddisease or condition is anxiety, schizophrenia, mania or manicdepression.
 19. A method of treatment or prophylaxis of neurologicaldisorders, psychotic disorders or intellectual impairment disorders,which comprises administering a therapeutically effective amount of apharmaceutical composition according to claim
 16. 20. The method ofclaim 18, wherein said disorder is Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder, Parkinson's disease, Huntington'sdisease, Tourette's syndrome, neurodegenerative disorders in which thereis loss of cholinergic synapses, jetlag, nicotine addiction, craving,pain, or ulcerative colitis.
 21. A method for inducing the cessation ofsmoking comprising administering an effective amount of a pharmaceuticalcomposition according to claim
 16. 22. The use of a compound accordingto claim 1, an enantiomer thereof or a pharmaceutically-acceptable saltthereof, in the manufacture of a medicament for the treatment orprophylaxis of human diseases or conditions in which activation of thealpha-7 nicotinic receptor is beneficial selected from neurologicaldisorders, psychotic disorders, intellectual impairment disorders,Alzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, Attention Deficit Hyperactivity Disorder, anxiety,schizophrenia, mania or manic depression, Parkinson's disease,Huntington's disease, Tourette's syndrome, or neurodegenerativedisorders in which there is loss of cholinergic synapses.
 23. The use ofa compound or a pharmaceutically-acceptable salt thereof according toclaim 1, in the manufacture of a medicament for the treatment orprophylaxis of jetlag, pain, or ulcerative colitis or to facilitate thecessation of smoking or the treatment of nicotine addiction or cravingincluding that resulting from exposure to products containing nicotine.